Cerebral edema contributes significantly to morbidity and mortality in patients with traumatic brain injury, stroke, and other nervous system disorders. However, treatments are limited and the mechanisms are poorly understood. The long-term goal of this research is to identify those mechanisms and to develop a more effective treatment for cerebral edema. Recent compelling evidence has shown that the major brain water channel, aquaporin-4 (AQP4), which is abundantly expressed in astrocytes at the blood-brain and brain-CSF barriers, may contribute to the development of cerebral edema. The central hypothesis is that AQP4 plays a fundamental role in astrocyte swelling and development of cerebral edema. Three aims are proposed to test this hypothesis. Aim 1 will examine the role of AQP4 in the development of cerebral edema in a model of traumatic brain injury. Brain water content, intracranial pressure, neurological function, and outcome will be compared in wildtype mice and AQP4 null mice following brain trauma. Aim 2 will investigate the role of AQP4 in cellular edema and extracellular space properties in wildtype and AQP4 null brain slices using gravimetric, optical, and iontophoretic techniques. Aim 3 will focus on comparative analyses of cell volume and ion flux in primary astrocyte cultures from wildtype mice and AQP4 null mice at baseline and in response to pathological stimuli that induce cell swelling. The proposed research should provide definitive, mechanistic data on the role of AQP4 in the development of cerebral edema. If AQP4 is proven to be important, as anticipated, then modulation of AQP4 function could provide a novel therapeutic strategy for the treatment of cerebral edema.